The present disclosure relates to neural stimulation and, more particularly, to selective activation of targeted predetermined neurons through high-frequency electrical stimulation.
In the healthy retina, light is converted into very complex patterns of spatiotemporal signaling. Specifically, retinal ganglion cells (RGCs), the output neurons of the retina, generate complex patterns of action potentials that are carried to higher visual centers. There are different types of RGCs (at least twelve different types in the mammalian retina) and each type elicits a different pattern of action potentials to convey information. For example, some RGCs respond strongly to the onset of a light stimulus (referred to as ON cells) while others remain quiet when a light stimulus is turned on but respond strongly when the stimulus is turned off (referred to as OFF cells). Accordingly, many closely situated ganglion cells can each generate a different spiking response to a given stimulus simultaneously.
Outer retinal degenerative diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP) affect the vision of over a million people in the United States and many more worldwide. These diseases target the outer retina and typically result in the loss of function of the light-sensitive photoreceptors, thereby decreasing the light responsiveness of the eye. RGCs, as well as other neurons in the inner retina, are thought to survive the degenerative process and one of the key approaches in the field of retinal prosthetics is to optimize the way in which these surviving retinal neurons are stimulated.
There has been considerable progress in this field over the last decade, leading to the implementation of several clinical trials using retinal prosthetic devices. Some retinal prosthetics include arrays of stimulating electrodes positioned either at the inner or outer surface of the retina. Individual electrodes within the array are activated independently with the goal of creating meaningful patterns of spiking in the surviving neurons within the region around the electrode. Simultaneous activation of multiple electrodes is used to create percepts that have more complex spatial detail. Patients in these clinical trials have reported visual percepts arising from stimulation and some have even been able to perform simple tasks such as identifying household objects, performing limited navigation, and reading simple words. While this progress is highly encouraging, many aspects of overall performance remain somewhat limited. For example, even the fastest reading rates were restricted to only a few words per minute, and the average rate across all patients was much slower.
Although it is not entirely clear why device performance is limited, one likely factor is the use of suboptimal stimulation methods. For example, the acuity of normal vision is typically quite high because tightly-packed RGCs, especially in the fovea, each extract information from only a narrow portion of visual space. In contrast, the diameter of stimulating electrodes used in existing implanted devices can be up to 200 micrometers (μm). As a result, each electrode can stimulate tens or even hundreds of RGCs, thereby greatly reducing resolution. In addition, as described above, the retina contains different types of RGCs, such as ON cells and OFF cells, and each type extracts different features of the visual world and transmits this information to higher visual centers using distinct patterns of spiking. Ideally, a retinal prosthetic would replicate the above-described (natural) pattern of signaling, that is, separately activating the ON ganglion cells in a given patch of retina without simultaneously activating the OFF ganglion cells in the same region. However, due to the close proximity of different RGCs to one another, stimulation from any given electrode in existing prosthetic devices is likely to elicit spiking patterns in multiple RGC types simultaneously, thereby sending a signal to the brain that is non-physiological.
Recent work has shown some progress toward selective activation of RGC types. For example, a recent study used a multicapacitor array to hyperpolarize photoreceptor terminals, mimicking the physiological ON retinal response. However, targeting of photoreceptor terminals may limit the utility of such an approach due to photoreceptor degeneration in most patients that would be candidates for retinal prostheses. Similarly, another recent study was able to create differential responses in ON and OFF cells using sinusoidal stimulation. They too surmised that the ON/OFF differences were the result of photoreceptor activation (again limiting the utility of their approach). Yet another study found that ON cell populations in rabbit retina have lower stimulus thresholds than OFF cells in response to monophasic cathodal stimuli applied subretinally. These results did not extend to mouse retina however, raising questions as to its generality and therefore its suitability for clinical use.
Therefore, it would be desirable to provide a clinically useful device and methods capable of eliciting retinal response that better mimics physiological retinal output. New stimulation methods and devices that could provide more precise control over elicited neural activity, such as preferential targeting of specific RGC types, would bring the elicited retinal response more in line with physiological retinal output and, thus, lead to better clinical outcomes.